We propose a novel approach to understanding the pathophysiology of Attention- Deficit/Hyperactivity Disorder (ADHD) by linking a neural circuit associated with attentional lapses to increased intra-subject response time variability. Based on our preliminary data, we hypothesize the presence of ADHD-related abnormalities in functional connectivity (regional temporal coherence) in a circuit linking dorsal anterior cingulate cortex (dACC) to the retrosplenial complex (RSC;comprising posterior cingulate cortex and precuneus). We propose to characterize this novel candidate locus of dysfunction in a sample of 50 right-handed unmedicated adults with current ADHD and a lifetime history of combined-type ADHD and 50 sex-, age-, IQ-, socioeconomic status-, and handedness-matched healthy comparisons. We will (1) use fMRI to replicate our preliminary findings of ADHD-related decreases in dACC/RSC functional connectivity strength;(2) assess group differences in the structural integrity of the dACC/RSC circuit using diffusion tensor imaging (DTI), and (3) relate functional and structural measures of circuit integrity to intra-individual response time variability during two response tasks during scanning. We will also obtain a comprehensive battery assessing nearly all putative neuropsychological deficits in ADHD in order to explore the relationships between intra-subject variability, brain circuitry abnormalities, and neuropsychological deficits in ADHD. This proposal, which combines novel methods, novel specific hypotheses, and substantial preliminary data, has the potential to delineate brain-behavior relationships that will inform translational models of pathophysiology of this common and highly impairing disorder. PUBLIC HEALTH RELEVANCE: We propose to apply novel neuroimaging methods to better understand the brain mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD). Individuals with ADHD are highly inconsistent in their responses, and we will study a brain circuit that is associated with such inconsistency in 50 adults with ADHD and 50 healthy subjects. We will also measure key mental abilities that are suspected of being involved in ADHD, including alertness, working memory, ability to suppress unwanted responses, ability to shift mental set, and ability to time brief intervals. The proposed study has the potential to teach us about function and dysfunction of specific brain circuits in ADHD, a common and impairing condition. This information is needed to improve methods of diagnosis and to develop new treatments.